The Fragile X syndrome, the most common inherited form of mental disability, is caused by transcriptional inactivafion ofthe FMRI gene. FMRI encodes FMRP, an RNA-binding protein that associates with about 1000 mRNAs in the brain. FMRP represses mRNA translation by impeding ribosome translocation, thereby reducing the rate of polypeptide elongation. Thus in the absence of FMRP, protein synthesis in the brain is aberrantly high, which causes the disease. CPEB is a second RNA binding protein in the brain, but instead of repressing translation like FMRP, it stimulates translation by inducing cytoplasmic polyadenylation. The FMRP knockout (KO) mouse is an exceptionally useful tool for studying Fragile X. FMRP/ CPEB double (dKO) mice display re-balanced translation in the brain such that overall rates of protein synthesis are normal. Moreover, all measured electrophysiolgoical, morphological, and behavioral phenyoptes that are defective in FMRP KO mice are rescued to wild type (WT) or near WT levels in dKO mice. Acute depletion of CPEB in the hippocampus of adult FMRP KO mice rescues hippocampus-dependent working memory. The rate of polypeptide elongation is restored to WT levels in FMRP/CPEB dKO brains, demonstrating that ribosome translocation is the underlying molecular defect causing the Fragile X syndrome. Aim 1 tests the hypothesis that CPEB-associated factors that comprise the cytoplasmic polyadenylation complex are also involved in FMRP regulated translation, behavior, and synapse function. Aim 2 employs a novel genomewide method to identify the mRNAs whose translation is rescued in FMRP/CPEB dKO brains. Aim 3 employs another new genome-wide method to test the hypothesis that the polyadenylation of specific mRNAs is necessary for rescue of Fragile X phenotypes in FMRP/CPEB dKO brains. These studies will address the molecular causes of Fragile X and will indicate novel therapies to treat the disease.